Satellite Symposium

“Guidelines on Prevention and Treatment of Cancer-Associated Thrombosis”

Stockholm, September 16, 2008

The Art of Medical Prophylaxis, Impacting the Patient Early

Anna Falanga, MD Hemostasis and Thrombosis Center Hematology-Oncology Dept Ospedali Riuniti Bergamo, Italy

Medical Conditions

• Although VTE is most often considered to be associated with recent surgery or trauma, 50 to 70% of symptomatic thromboembolic (TE) events and 70 to 80% of fatal pulmonary embolism (PE) occur in non-surgical patients 1 • PE accounts for 5-10% of deaths in hospitalized patients, making VTE the most common preventable cause of in hospital death 2 Adapted from: 1. ACCP 2004. 1.Geerts WH, et al.

Chest.

2004;126:S338 –S400, 2. Cohen A et al.

Lancet

2008:371;387-394 .

Venous Thromboembolism (VTE) Risk

• Hospitalized medical cancer patients are at increased risk for VTE • Out of hospital cancer patients receiving therapy are at risk for VTE

VTE Prevention: We are Failing Our Patients Cancer: 2001 FRONTLINE Survey 1 — 3891 Respondents 30 20 10 0 60 50 40 52 Surgical Onc 5 Medical Onc 30 33 US 91 Canada 01 29 US 02 28 UK 03 43 50 US 07 World 07

Adapted from: 1. Kakkar AK et al.

Oncologist

. 2003;8:381-88.

2. Anderson FA et al.

Ann Intern Med

. 1991;115:591-95. 3. Rahim SA et al.

Thromb Res

. 2003;111:215-19 4. Goldhaber SZ et al.

Am J Cardiol

. 2004;93:259-62.

5. Rashid

J Royal Soc Med

2005.

6. Spencer FA et al.

Arch Intern Med

2007;167:1471-75.

7. Tapson VF, et al.

Chest

2007;132:936-45.

Recommendations for VTE Prophylaxis in Patients with Cancer Released by International Medical Oncology Societies

• AIOM (Italian Medical Oncology Society) - 2006 • ASCO (American Society of Clinical Oncology) - 2007 • NCCN (National Comprehensive Cancer Network) - 2007, 2008 • ESMO (European Society of Medical Oncology) - 2008

Recommendations for VTE Prophylaxis in Hospitalized Patients with Cancer

• Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation

Contraindications to Anticoagulation

• Active, uncontrollable bleeding • Active cerebrovascular hemorrhage • Dissecting or cerebral aneurysm • Bacterial endocarditis • Pericarditis, active peptic or other GI ulceration • Severe, uncontrolled or malignant hypertension • Severe head trauma • Pregnancy (warfarin) • Heparin-induced thrombocytopenia (heparin, LMWH) • Epidural catheter placement.

Prophylaxis in Acutely I ll Medical Patients

• No randomized clinical trials designed

a priori

hospitalized medical cancer patients for • Randomized, placebo-controlled trials in acutely ill hospitalized medical patients – MEDENOX 1 - enoxaparin 40 mg daily – PREVENT 2 - dalteparin 5000U daily – ARTEMIS 3 - fondaparinux 2.5 mg daily Adapted from: 1. Samama et al.

N Engl J Med

1999;341:793-800; 2. Leizorovicz et al.

Circulation

2004;110:874-79; 3. Cohen et al.

Blood

2003; 102(11): 15.

Thromboprophylaxis of Medical Patients: Clear Benefits Over Placebo Study NNT Prophylaxis Patients with VTE, %

MEDENOX P <0.001

PREVENT P =0.0015

ARTEMIS 3 P =0.029

2 1 10 45 20 Placebo Enoxaparin 40 mg Placebo Dalteparin Placebo Fondaparinux *VTE at day 14; † VTE at day 21; ‡ VTE at day 15.

14.9

* (n=288) 5.5 (n=291) 5.0 (n=1,473) † 2.8 (n=1,518) 10.5

‡ (n=323) 5.6 (n=321) NNT = number needed to treat; RRR = relative risk reduction.

Adapted from: 1 Samama et al.

N Engl J Med

2 Leizorovicz et al.

Circulation

1999;341:793-800.

2004;110:874-9.

3 Cohen et al.

Br Med J

2006.

Proximal DVT + Symptomatic VTE at D14-21 MEDENOX

Enox.

2.1 %

Placebo

6.6 %

P

= 0.037

PREVENT

Dalte.

2.6 %

Placebo

5.0 %

P

= 0.002

ARTEMIS

Fond.

1.5 %

Placebo

3.4 %

P

= 0.085

EXCLAIM: Study Design

Enoxaparin 40 mg s.c. q.d.

Enoxaparin 40 mg s.c. q.d.

R Days 10 ±4   Prospective, randomized, double-blind 5,090 patients: enrollment completed Placebo 6-month follow-up 38 ±4 Systematic Duplex ultrasound

Inclusion Criteria Initial inclusion criteria Age



40 years Recent immobilization (



3 days)

• • •

Acute medical illness

Heart failure, NYHA class III/IV Acute respiratory insufficiency Other acute medical conditions including: – – – post-acute ischemic stroke acute infection without septic shock active cancer

Amended inclusion criteria

Level 1 mobility (total bed rest or sedentary patients)

or

Level 2 mobility (Level 1 with bathroom privileges) Adapted from Hull et al.

J Thromb Thrombolysis.

2006; 22:31-38.

+

• • • Age > 75 years OR History of VTE OR Diagnosis of cancer

Summary of Efficacy and Safety: End of the Double-blind Period Placebo (N=1681 efficacy pop; N=2027 safety pop) Enoxaparin (N=1666 efficacy pop; N=2013 safety pop) 6 5 P=0.0011

NNT 46 4.90

P=0.019

4 3 2.80

P=0.0109

NNT 121 NNH 224 2 1.00

1 0.30

0.15

0.60

0 VTE events

NNT = number needed to treat NNH = number needed to harm

Symptomatic DVT Major bleeding

Recommended Dose: Venous Thromboembolism Prophylaxis Management Prophylaxis Drug Patients with cancer receiving medical or surgical treatment while staying in hospital Unfractionated Heparin (UFH) Dalteparin Enoxaparin Fondaparinux Regimen 5000 U q 8 h 5000 U daily 40 mg daily 2.5 mg daily

Prophylaxis in Medical Patients: Ambulatory Cancer Patients

• The role of thromboprophylaxis in ambulatory cancer patients during chemotherapy and hormone therapy is not established. • One double-blind placebo-controlled RCT demonstrated the efficacy of low-intensity warfarin (INR 1.3-1.9) in patients receiving chemotherapy for metastatic breast cancer (Levine MN et al,

Lancet

1994).

Double Blind Randomized Trial of Very-low-dose Warfarin (INR 1.3 1.9) for Prevention of Thromboembolism in Stage IV Breast Cancer Patients * Thromboembolic events Warfarin n=152 1 Placebo n=159 7 relative risk reduction = 85% * women receiving chemotherapy for metastatic breast cancer p= 0.031

Adapted from Levine et al.,

Lancet

1994.

Warfarin Prophylaxis: Limitations

• Very difficult schedule • Interaction with cytotoxics • Tested only in breast cancer

Prophylaxis of VTE in Medical Cancer Patients

• LMWH benefits – Predictable anticoagulant effect – Single daily administration – Reduced toxicity (thrombocytopenia, osteoporosis) – Acceptable safety profile in oncological patient (long term use in recent studies: FAMOUS, CLOT)

Primary Prophylaxis During Chemotherapy: LMWH Recent Closed Studies Study TOPIC-1 1 TOPIC-2 1 PRODIGE 2 PROTECHT Cancer Breast Cancer Non small cell lung cancer Malignant glioma (grade III or IV) Lung, Breast, Gastrointestinal, Ovarian, Head/Neck cancer

Adapted from: 1 Haas

J Tromb Haemost

2005, suppl. 1, Abs OR059; 2 Perry et al.

Thromb Res

2007, suppl. 2, Abs PO40.

Primary Prophylaxis During Chemotherapy: LMWH Ongoing Studies AUTHOR STUDY

Pancreatic cancer

SCHEDULE Maraveyas Prospective randomised Gemcitabine ± Dalteparin 200U/Kg o.d.

Pelzer Prospective randomised Gemcitabine ± Enoxaparin 1 mg/Kg

Adapted from ASCO 2007.

Recommendations for Primary VTE Prophylaxis in Ambulatory Patients with Cancer

• Current guidelines do not recommend: – Routine prophylaxis with an antithrombotic agent in ambulatory cancer patients

Special consideration: Prophylaxis in Multiple Myeloma patients

• Prophylaxis with LMWH or adjusted dose warfarin (INR~1.5) is recommended in multiple myeloma patients receiving thalidomide or lenalidomide + chemotherapy or dexamethasone (high VTE risk). • However: – No RCTs available – Recommendation is based on extrapolation from non randomized trials or randomized studies in other similar high risk categories – Well-designed RCTs are urgently needed Adapted from ASCO Guidelines,

JCO

2007.

Central Venous Catheter (CVC) – Related Thrombosis

Prophylaxis of CVC - Related Thrombosis

• The presence of CVC is a risk factor for VTE.

• Three recent clinical trials have assessed that the incidence of CVC-related symptomatic thrombosis is approximately 3% to 4%.

• These trials failed to show a significant effect of prophylaxis with 1 mg fixed dose warfarin, or LMWH dalteparin, or LMWH enoxaparin in reducing symptomatic and asymptomatic thrombosis in patients with cancer.

Randomised Controlled Clinical Trials of Prophylaxis of CVC - Related Thrombosis Study Karthaus M et al *

Ann Onc 2006

Couban S et al *

JCO 2005

Verso M et al °

JCO 2005

* Symptomatic events ° Routine venography at 6 weeks

Drug Dalteparin, 5000 IU od Placebo Warfarin, 1 mg od Placebo Enoxaparin, 40 mg od Placebo n.

285 140 130 125 155 155 CRT (%) 11 (3.7) 5 (3.4) 6 (4.6) 5 (4.0) 22 (14.2) 28 (18.1)

Recommendations for Prophylaxis for CVC – Related Thrombosis

• Current guidelines agree that extensive, routine prophylaxis to prevent CVC-related VTE is not recommended. To date prophylaxis might be tailored according to individual risk level.

Conclusion

• Evidence from epidemiological and clinical studies demonstrates that not only surgical patients but also medical patients with acute medical conditions and predisposing risk factors are at significant risk of VTE.

• Hospitalized cancer patients should be assessed for risk of VTE and given appropriate thromboprophylaxis.

• Early intervention with thromboprophylaxis (i.e. LMWH) will impact cancer patient outcome.